Original Article Identification of a Novel Twinkle Mutation in a Family With Infantile Onset Spinocerebellar Ataxia by Whole Exome Sequencing Halil Dündar PhD a, 1 ,Rıza Köksal Özgül PhD a, b, 1 , Dilek Yalnızo  glu MD c , Sevim Erdem MD d , Kader Karlı O  guz MD e , Deniz Tuncel MD f , Ça  grı Mesut Temuçin MD d , Ali Dursun MD, PhD a, * a Metabolism Unit, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Sıhhiye, Ankara, Turkey b Institute of Child Health, Hacettepe University, Sıhhiye, Ankara, Turkey c Department of Child Neurology, Faculty of Medicine, Hacettepe University, Sıhhiye, Ankara, Turkey d Department of Neurology, Faculty of Medicine, Hacettepe University, Sıhhiye, Ankara, Turkey e Department of Radiology, Faculty of Medicine, Hacettepe University, Sıhhiye, Ankara, Turkey f Department of Neurology, Faculty of Medicine, Sütçü _ Imam University, Kahramanmaras ¸ , Turkey article information Article history: Received 19 October 2011 Accepted 22 December 2011 abstract Whole exome sequencing combined with homozygosity mapping comprises a genetic diagnostic tool to identify genetic defects in families with multiple affected members, compatible with presumed autosomal recessively inherited neurometabolic/neurogenetic disease. These tools were applied to a family with two individuals manifesting ataxia, associated with peripheral sensory neuropathy, athetosis, seizures, deaf- ness, and ophthalmoplegia. A novel homozygous missense mutation c.1366C>G (L456V) in C10orf2 (the Twinkle gene) was identified, confirming infantile onset spinocerebellar ataxia in the probands. Signs in infantile onset spinocerebellar ataxia follow a fairly distinct pattern, affecting early development, followed by ataxia and loss of skills. However, this very rare disease was previously reported only in Finland. We suggest that infantile onset spinocerebellar ataxia should be more frequently considered in the differential diagnosis of neurometabolic diseases in childhood. Next-generation sequencing and its use along with homozygosity mapping offer highly promising techniques for molecular diagnosis, especially in small families affected with very rare neurometabolic disorders such as infantile onset spinocerebellar ataxia. Ó 2012 Elsevier Inc. All rights reserved. Introduction Neurogenetic/neurometabolic disorders exhibit a wide and complex spectrum of clinical manifestations varying within and between families, with the wide range of clinical and genetic heterogeneity of these diseases increasing their diagnostic challenge. In addition, more than one autosomal recessive disorder may be evident in a family, especially in populations with high rates of consanguineous marriages, which may further complicate the genetic identification of a specific disease. Although traditional positional cloning has been the major tool for identifying disease genes in these situations, the presence of locus heterogeneity, small family size, and an abundance of candidate genes in the mapped chromosomal regions have limited the yield of this technique. Recently developed combinational strategies, using next-generation sequencing along with homozygosity mapping, have provided a strong and efficient approach in such circumstances [1,2]. We report on a Turkish family containing two live, affected members with diverse neurologic signs including intellectual disability, deafness, sensory ataxia impaired gait attributed to peripheral neuropathy, ophtalmoplegia, and orobuccolingual dyski- netic movements. Using a combined approach of homozygosity mapping followed by exome array sequencing, we identified a novel missense mutation in C10orf2 gene, encoding the Twinkle protein. Mutations in this gene cause a very rare Finnish disease, infantile onset spinocerebellar ataxia (IOSCA). This study demonstrates that exome sequencing analysis offers a very powerful method to discover the genetic loci of the rare genetic diseases, and to diagnose very rare diseases such as infantile onset spinocerebellar ataxia. Materials and Methods Patients The study group involves a Turkish family from middle-eastern Turkey, con- sisting of eight people, including parents who are relatives. A detailed clinical evaluation was performed in all family members. Of six siblings, two individuals * Communications should be addressed to: Dr. Dursun; Metabolism Unit; Department of Pediatrics; Faculty of Medicine; Hacettepe University; Sıhhiye, 06100, Ankara, Turkey. E-mail address: adursun@hacettepe.edu.tr 1 Both authors contributed equally to this report. Contents lists available at ScienceDirect Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu 0887-8994/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2011.12.006 Pediatric Neurology 46 (2012) 172e177